Breast cancer is the most frequent malignancy in women. A family history of this disease is generally found in approximately 10% of patients afflicted with this disease. In addition, ovarian cancer is the gynecologic tumor with the highest mortality secondary to its insidious onset. A family history of this disease is generally found in approximately 3-5% of patients afflicted with this disease (Koch et al, In. J. Epidemiol., 18:782-785 (1989)). It is these limited groups of patients that will probably benefit most from the recent isolation of the breast cancer gene BRCA-1 (Miki et al, Science, 266:66-71 (1994); and Futreal et al, Science, 266:120-122 (1994)), which offers a likely inroad to a more accurate individual risk assessment in these individuals. The remaining majority of the women at risk have so far been assessed regarding their likelihood to contract these malignancies solely on the basis of anamnestic variables listed in Table 1 (ovarian cancer) and Table 2 (breast cancer) below. Table I represents a meta-analysis of 48 publications, while Table II represents a meta-analysis of 32 publications.
TABLE 1 __________________________________________________________________________ Risk Factors for 95% Confidence Ovarian Cancer Cases Controls Sensitivity Specificity Odds Ratio Interval __________________________________________________________________________ Years of 2857 10328 0.24 0.67 0.7 (0.60-0.73) Education (&lt;12) High Social Class 477 1251 0.26 0.81 1.4 (1.11-1.84) Age of 6493 26904 0.27 0.73 1.0 (0.95-1.07) Menarche (&lt;12) Age at Natural 1020 3085 0.22 0.79 1.1 (0.89-0.25) Menopause (&lt;53) Nulliparity 8554 32877 0.22 0.85 1.6 (1.49-1.68) Nulligravidity 3334 14852 0.21 0.87 1.8 (1.60-1.95) Age at First 3046 13120 0.16 0.90 1.6 (1.40-1.76) Birth (&lt;30) No Breast Feeding 4349 12909 0.32 0.57 0.6 (0.60-0.70) Years of 2263 11489 0.36 0.74 1.5 (1.40-1.69) Ovulation (&lt;35) No Use of Oral 6377 26345 0.74 0.42 2.1 (1.97-2.23) Contraceptives Family History of 2385 8057 0.3 0.99 3.7 (2.64-5.23) Ovarian Cancer in First Degree Relative Family History of 493 2465 0.7 0.98 3.3 (2.13-5.14) Ovarian Cancer in First Degree Relative or Second Degree Relative Family History of 752 2023 0.7 0.95 1.6 (1.17-2.34) Breast Cancer in First Degree Relative or Second Degree Relative Family History of 750 2023 0.5 0.96 1.2 (0.79-1.73) Endometrial Cancer in First Degree Relative or Second Degree Relative Family History of 5180 17672 0.5 0.98 2.4 (1.99-2.79) Ovarian, Breast or Endometrial Cancer in First Degree Relative or Second Degree Relative Alu Insertion 65 443 0.42 0.78 2.6 (1.49-4.42) in INTRON G __________________________________________________________________________
TABLE 2 __________________________________________________________________________ Risk Factors for 95% Confidence Breast Cancer Cases Controls Sensitivity Specificity Odds Ratio Interval __________________________________________________________________________ Atypical Hyperplasia 3986 4100 0.2 0.99 2.3 (1.56-3.43) of Breast Family History of 11117 11305 0.14 0.94 2.3 (2.09-2.51) Breast Cancer in First Degree Relative Family History of 3408 2914 0.11 0.96 2.7 (2.19-3.31) Breast Cancer in First Degree Relative or Second Degree Relative Family History of 3411 2914 0.2 0.99 1.4 (0.91-2.26) Ovarin Cancer in First Degree Relative or Second Degree Relative Family History of 3408 2914 0.4 0.96 1.2 (0.93-1.54) Endometrial Cancer in First Degree Relative or Second Degree Relative No Lactation 8095 20652 0.40 0.79 2.6 (2.46-2.75) Use of Oral 4941 5547 0.56 0.44 1.0 (0.92-1.07) Contraceptives Age of 7342 7000 0.22 0.80 1.1 (1.00-1.18) Menarche (&lt;12) Nulliparity 17124 1963310 0.19 0.85 2.4 (1.33-1.44) Age at First 10062 1575465 0.28 0.83 1.9 (1.80-1.97) Birth (&lt;30) Alcohol Intake 519 1182 0.17 0.86 1.2 (0.92-1.62) (&lt;20 g/day) Hair Dye Use 391 780 0.25 0.78 1.2 (0.88-1.56) Alu Insertion 164 443 0.28 0.78 1.37 (0.91-2.06) in INTRON G __________________________________________________________________________
Estrogen and progesterone receptor expression in the tumor itself have been established as prognostic factors (McGuire, Rec. Prog. Horm. Res., 36:135-149 (1980); Kieback et al, Cancer Research, 53:5188-5192 (1993); and Kieback et al, Anticancer Research, 13:2489-2496 (1993)). Also, somatic mutations in the progesterone receptor gene have been described in this context (Fuqua et al, J. Natl. Cancer Inst., 83:1157-1160 (1991); and Kieback et al, Berichte Gynakologie und Geburtshilfe, 127:1020 (1990)). However, there has been a lack of information on the existence and possible clinical and biological significance of genomic alterations in steroid receptor genes.
Recently, a genomic factor has been described that would permit further stratification. That is, a genomic Restriction Fragment Length Polymorphism (RFLP) in the human progesterone receptor gene located on the long arm of chromosome 11 (Law et al, Proc. Natl. Acad. Sci., USA, 84:2877-2881 (1987); and Rousseau-Merk et al, Hum. Genet., 77:280-282 (1987)) has been discovered (Genome Data Base #G00-390-114). Its clinical association with ovarian and breast cancer have recently been demonstrated to be associated with an Alu insertion within INTRON G of the human progesterone receptor gene (McKenna et al, Brit. J. Cancer, 71:451-455 (1995); and Rowe et al, Cancer Res., 55:2743-2745 (1995)).
The Alu insertion is in an intron which does not cause a change in the receptor protein. However, changes in the protein are biologically important for the development of disease, as well as for tumor cell growth. Thus, in the present invention, the exons of the progesterone receptor gene were screened for mutations. Point mutations in EXON 4 and EXON 5 were discovered in the present invention to be associated with the Alu insertion in INTRON G, and thereby with an increased risk for breast cancer and ovarian cancer. In all of the cases evaluated, these three mutations were found to simultaneously occur.